The infection of a patient with a pathogen remains a frequent, costly, and serious problem in health care despite advances in medical technology. For example, reactivation or infection with human viruses such as Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes simplex virus (HSV), Hepatitis viruses A, B, and C, and BK virus (BKV) markedly limit the success of organ and/or allogeneic stem cell transplantation (alloSCT). Taking the example of CMV, infection and disease results in life threatening complications following alloSCT and/or organ transplantation, even with appropriate use of anti-viral agents. Reactivation of CMV is associated with and augments acute graft-versus-host disease (GvHD) and organ rejection. Treatment of GvHD with immunosuppression enhances the cycle of further CMV reactivation. None of the current strategies are completely effective in preventing or treating CMV infections after transplantation.
Immunotherapy has been studied as an alternative strategy to treat CMV disease post-alloSCT. Polyclonal intravenous immunoglobulin (IVIG) and CMV-specific IVIG (Cytogam®) have been used with little success. Himawan (US Pre-Grant Pub. No. 2004/0234521) has studied the use of a polyclonal antibody directed against a pathogen conjugated to an anti-c3b antibody as a means for clearing pathogen from the circulation. This approach, while demonstrating limited success in exploiting the complement system to clear free floating pathogen from the circulation does not address the issue of treating cells infected with the pathogen.
Immunotherapy with CMV-specific donor-derived or engineered cytotoxic T-lymphocytes (CTL) has been tried since 1990s, but is yet to be translated to routine clinical use. For example, post-alloSCT infusions of cloned donor CMV-specific cytotoxic T lymphocytes (CTL) are dose-limiting, time-restricted, expensive, labor intensive, and have yet to produce any meaningful anti-CMV T cell response in immunocompromised hosts. See, Walter et. al., NEJM. 1995.
Previous studies in the field of cancer therapy have indicated that activated T-cells (ATC) can be redirected to tumor cells using bispecific antibodies against various malignancies. For example, armed ATC directed at Her2/neu, EGFR, CD20, and CD33 have been used to target prostate, lung, pancreas, head and neck, and ovarian cancer as well as multiple myeloma, non-Hodgkin's lymphoma, and acute myelogenous leukemia. See, e.g. Davol, et al., Clin Prostate Cancer 2004; Reusch, et al., Clin Cancer Res. 2006; Chan, et al., Clin Cancer Res. 2006. Similar attempts for targeting virally infected cells have met with limited success due to the difficulty in identifying or generating an antibody against an antigen of the pathogen that is expressed on the surface of an infected cell and is not subject to antigenic drift. See, e.g., Moran, et al., (1991) J. Immunol. 146(1):321-326; Fernandez-Sesma, et al. (1996) J. Virol. 70(7):4800-4804; and Fernandez-Sesma, et al., (1998) J. Immunol. 160:1841-1849.
Thus, there is a need for an effective, safe non-toxic therapy for treating patients suffering pathogenic infection or reactivation. The instant invention addresses this and other needs by providing for novel compositions and methods that dramatically improve the treatment and management of patients infected with a pathogen.